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      Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease

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          Abstract

          CLN5 neuronal ceroid lipofuscinosis (NCL, Batten disease) is a rare, inherited fatal neurodegenerative disorder caused by mutations in the CLN5 gene. The disease is characterised by progressive neuronal loss, blindness, and premature death. There is no cure. This study evaluated the efficacy of intracerebroventricular (ICV) delivery of an adeno-associated viral vector encoding ovine CLN5 (scAAV9/oCLN5) in a naturally occurring sheep model of CLN5 disease. CLN5 affected (CLN5 −/−) sheep received low, moderate, or high doses of scAAV9/oCLN5 at three disease stages. The treatment delayed disease progression, extended survival and slowed stereotypical brain atrophy in most animals. Of note, one high dose treated animal only developed mild disease symptomology and survived to 60.1 months of age, triple the natural life expectancy of an untreated CLN5 −/− sheep. Eyesight was not preserved at any administration age or dosage. Histopathologic examination revealed that greater transduction efficiency was achieved through higher ICV doses, and this resulted in greater amelioration of disease pathology. Together with other pre-clinical data from CLN5 −/− sheep, the safety and efficacy data from these investigational new drug (IND)-enabling studies supported the initiation of the first in-human CLN5 gene therapy clinical study using the ICV delivery route for the treatment of CLN5 NCL.

          Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05228145

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          Most cited references38

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          3D Slicer as an image computing platform for the Quantitative Imaging Network.

          Quantitative analysis has tremendous but mostly unrealized potential in healthcare to support objective and accurate interpretation of the clinical imaging. In 2008, the National Cancer Institute began building the Quantitative Imaging Network (QIN) initiative with the goal of advancing quantitative imaging in the context of personalized therapy and evaluation of treatment response. Computerized analysis is an important component contributing to reproducibility and efficiency of the quantitative imaging techniques. The success of quantitative imaging is contingent on robust analysis methods and software tools to bring these methods from bench to bedside. 3D Slicer is a free open-source software application for medical image computing. As a clinical research tool, 3D Slicer is similar to a radiology workstation that supports versatile visualizations but also provides advanced functionality such as automated segmentation and registration for a variety of application domains. Unlike a typical radiology workstation, 3D Slicer is free and is not tied to specific hardware. As a programming platform, 3D Slicer facilitates translation and evaluation of the new quantitative methods by allowing the biomedical researcher to focus on the implementation of the algorithm and providing abstractions for the common tasks of data communication, visualization and user interface development. Compared to other tools that provide aspects of this functionality, 3D Slicer is fully open source and can be readily extended and redistributed. In addition, 3D Slicer is designed to facilitate the development of new functionality in the form of 3D Slicer extensions. In this paper, we present an overview of 3D Slicer as a platform for prototyping, development and evaluation of image analysis tools for clinical research applications. To illustrate the utility of the platform in the scope of QIN, we discuss several use cases of 3D Slicer by the existing QIN teams, and we elaborate on the future directions that can further facilitate development and validation of imaging biomarkers using 3D Slicer. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection.

            This study examines transgene expression and biodistribution of adeno-associated virus (AAV) pseudotyped 1-9 after tail vein (TV) injection in male mice. Using a cytomegalovirus (CMV)-luciferase transgene, the time-course of expression in each animal was tracked throughout the experiment. The animals were imaged at 7, 14, 29, 56, and 100 days after the TV injection. The total number of photons emitted from each animal was recorded, allowing examination of expression level and kinetics for each pseudotyped virus. The bioluminescence imaging revealed three expression levels (i) low-expression group, AAV2, 3, 4, and 5; (ii) moderate-expression group, AAV1, 6, and 8; and (iii) high-expression group, AAV7 and 9. In addition, imaging revealed two classes of kinetics (i) rapid-onset, for AAV1, 6, 7, 8, and 9; and (ii) slow-onset, for AAV2, 3, 4, and 5. We next evaluated protein expression and viral genome copy numbers in dissected tissues. AAV9 had the best viral genome distribution and highest protein levels. The AAV7 protein and genome copy numbers were comparable to those of AAV9 in the liver. Most surprisingly, AAV4 showed the greatest number of genome copies in lung and kidney, and a high copy number in the heart. AAV6 expression was observed in the heart, liver, and skeletal muscle, and the genome distribution corroborated these observations.
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              Study of Intraventricular Cerliponase Alfa for CLN2 Disease

              Recombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme-replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                08 August 2023
                2023
                : 14
                : 1212228
                Affiliations
                [1] 1 Faculty of Agriculture and Life Sciences , Lincoln University , Lincoln, New Zealand
                [2] 2 Department of Radiology , University of Otago , Christchurch, New Zealand
                [3] 3 Department of Pediatrics , University of Texas Southwestern Medical Center , Dallas, TX, United States
                Author notes

                Edited by: Paschalis Nicolaou, The Cyprus Institute of Neurology and Genetics, Cyprus

                Reviewed by: Hemanth Ramesh Nelvagal, University College London, United Kingdom

                Bruce Frederic Smith, Auburn University, United States

                Nicolina Cristina Sorrentino, Telethon Institute of Genetics and Medicine (TIGEM), Italy

                *Correspondence: Nadia L. Mitchell, nadia.mitchell@ 123456lincoln.ac.nz
                Article
                1212228
                10.3389/fgene.2023.1212228
                10442658
                37614821
                89fd9b4a-2a47-4578-b7a0-c2c3c1fb85e2
                Copyright © 2023 Mitchell, Murray, Wellby, Barrell, Russell, Deane, Wynyard, Palmer, Pulickan, Prendergast, Casy, Gray and Palmer.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 June 2023
                : 24 July 2023
                Funding
                This work was funded by CureKids NZ (6501, 3607), the Canterbury Medical Research Foundation (01/2019), the Batten disease Support and Research Association (United States), Batten Disease New Zealand, Neurogene Inc. (all to DP and NM), and the Maurice and Phyllis Paykel Trust (to NM). A University of Otago Health Sciences post-doctoral fellowship and Lincoln University post-doctoral fellowship were awarded by NM and SM respectively.
                Categories
                Genetics
                Original Research
                Custom metadata
                Genetics of Common and Rare Diseases

                Genetics
                neuronal ceroid lipofuscinosis,neurodegenerative disease,gene therapy,adeno-associated virus,intracerebroventricular,sheep

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